A new technology has been developed for the creation of oral vaccines. This technology is based on the discovery of a polypeptide (ca. 50 kDa) that possesses the ability to bind and penetrate gut epithelial barriers. The specific steps in the process are: apical membrane binding;receptor-mediated endocytosis;transcytosis;and basolateral release. The polypeptide crosses epithelial barriers without undergoing any structural or functional modifications. The novel polypeptide domain can be utilized as a carrier device to transport heterologous substances into the body. Proof of concept has been achieved by linking the carrier to a host of substances that differ in size (mw= ca. 200 to ca. 45,000) and in biological activity (i.e., ligand, enzyme, antigen). The resulting carrier~cargo constructs have been shown to cross epithelial barriers in vitro (e.g. monolayers of human gut epithelial cells) and in vivo (e.g., mouse and rat models). In every case, the carrier~cargo constructs retained their native structure and their characteristic biological activity. A lead product has been identified that will utilize the new technology. This product will be a fusion protein that incorporates the carrier polypeptide linked to a tetanus antigen to create an oral vaccine against tetanus toxin. A series of studies will be performed with the lead product in anticipation of a formal meeting with the Food and Drug Administration. The major goals of the proposed studies will be: 1. To eliminate carrier binding to non-epithelial cells 2. To reduce or abolish the immunogenicity of the carrier 3. To confirm the efficacy of the non-neurotropic, non-immunogenic carrier 4. To demonstrate an absence of toxicity of the modified carrier and the modified carrier~tetanus antigen construct If successful, this work should demonstrate that a mucosal tetanus vaccine is worthy of evaluation as a clinical product.